2. Academic Validation
  3. Design, synthesis and evaluation of novel 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as potent, selective and reversible Bruton's tyrosine kinase (BTK) inhibitors for the treatment of rheumatoid arthritis

Design, synthesis and evaluation of novel 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as potent, selective and reversible Bruton's tyrosine kinase (BTK) inhibitors for the treatment of rheumatoid arthritis

  • Eur J Med Chem. 2019 May 1:169:121-143. doi: 10.1016/j.ejmech.2019.02.077.
Chufeng Zhang 1,  Heying Pei 1,  Jun He 1,  Jiali Zhu 1,  Weimin Li 2,  Ting Niu 3,  Mingli Xiang 4,  Lijuan Chen 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China.
  • 2 Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3 Department of Hematology and Research Laboratory of Hematology, West China Hospital of Sichuan University, Chengdu, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, 610041, China. Electronic address: [email protected].
PMID: 30875504 DOI: 10.1016/j.ejmech.2019.02.077
Abstract

A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized as reversible Btk inhibitors, and evaluated their kinase selectivity, anti-proliferation against the B-cell lymphoma cell lines (Ramos, Jeko-1) and cell line Btk enhanced (Daudi) in vitro. Among them, compound 28a exhibited the most excellent potency (IC50 = 3.0 nM against Btk enzyme, 8.52 μM, 11.10 μM and 7.04 μM against Ramos, Jeko-1, Daudi cells, respectively), good kinase selectivity and inhibited Btk Y223 auto-phosphorylation and PLCγ2 Tyr1217 phosphorylation. Importantly, 28a showed efficacy anti-arthritic effect on collagen-induced arthritis (CIA) model in vivo. 28a 60 mg/kg dose level once a day group displayed markedly reduced joint damage and cellular infiltration without any bone and cartilage morphology change.

Keywords

BTK; Inhibitor; Reversible; Rheumatoid arthritis.

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